1、Joint Meeting of the Arthritis and Drug Safety and Risk Management Advisory CommitteesFebruary 16-18, 2005太原房產(chǎn)網(wǎng) 52youjuP-1Leonard M. Baum, RPhVice President, Regulatory AffairsBayer HealthCareConsumer Care DivisionP-2AgendaRegulatory Overview NaproxenADAPT TrialSafety EvaluationClinical Pharmacology

2、Clinical Studies Postmarketing SurveillanceObservational StudiesConclusions3Roche/Bayer Presenters and RespondersPresenters: Leonard M. Baum, RPhVice President, Regulatory AffairsBayer HealthCareMartin H. Huber, M.D.Vice President, Global Head Drug Safety Risk ManagementHoffmann La-Roche Inc.Respond

3、ers:Susan Sacks, Ph.D.Global Head, EpidemiologyHoffmann La-Roche Inc.Bharat Thakrar, Ph.D.Senior EpidemiologistHoffmann La-Roche Inc.Ernst Weidmann, M.D.Head, Global SafetyBayer HealthCareSteve Zlotnick, Pharm.D.Director, Medical Affairs Bayer HealthCare4Outside ExpertsKay Brune, M.D.Professor and C

4、hairmanDepartment of Experimental and Clinical Pharmacology and ToxicologyFriedrich-Alexander University Erlangen - NurembergIan M. Gralnek, M.D., MSHSAssistant Professor of Medicine, Division of Digestive DiseasesDavid Geffen School of Medicine at UCLA5Regulatory Overview Naproxen available in the

5、United States since 1976Prescription currently marketed by multiple manufacturers for the treatment of RA, OA, ankylosing spondylitis, gout, juvenile RA, dysmenorrhea, tendinitis, bursitis, and painAleve (OTC) approved in 1994 Currently marketed by Bayer HealthCare for temporary relief of minor ache

6、s and pains, and for the temporary reduction of feverMultiple generic versions6NaproxenNaproxen, a nonsteroidal anti-inflammatory drug (NSAID), belongs to the chemical class propionic acid derivativesNaproxen has anti-inflammatory, analgesic and antipyretic propertiesNaproxen known to inhibit platel

7、et aggregationThe major differences between members of the NSAID class are potency and pharmacokinetics7Classes of NSAIDSSalicylic acid derivativesAspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisalPara-aminophenol derivativesAcetaminophenIndole and indene acetic acids

8、Indomethacin, sulindacHeteroaryl acetic acidsTolmetin, diclofenac, ketorolacPropionic acidsNaproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, oxaprozinAnthranilic acids (fenamates)Mefenamic acid, meclofenamic acidEnolic acidsOxicams (piroxicam, meloxicam)AlkanonesNabumetoneCoxibsCelecoxib, v

9、aldecoxib, rofecoxib (withdrawn)Source: Goodman and Gilmans The Pharmacological Basis of Therapeutics, 10th edition8Relevance of Naproxen DataThe safety profile for naproxen is well knownNaproxen is a reference drug for many analgesic clinical trialsNaproxen and other non-selective NSAIDs, are impor

10、tant treatment options for a broad range of patients and conditions9Naproxen Exposure Data (Rx and OTC)550,000,000 courses of therapy*110,000,000 ptsPost-marketing- 80,000 ptsObservational Studies 8,000 pts 10,000 ptsClinical TrialsOTCRX*courses of therapy (2 tab x 10 days)10The ADAPT TrialNIH spons

11、ored studyBayer provided naproxen sodium for investigational use Study DesignNaproxen sodium 220 mg bidCelecoxib 200 mg bidPlacebo Patient Population 2400 patients, age 70 years or older, for prevention of Alzheimers diseaseStudy DurationBegan in 2001, planned for 7 years, suspended after 3 yearsSou

12、rces: NIH News Dec 20, 2004; Washingtonpost Feb 1, 2005, written by Woloshin S et al.11Publicly Reported Events Leading to the Suspension of ADAPT DSMB review on Dec. 10, 2004 did not recommend stopping the study The APC study was suspended due to indications of an increase in cardiovascular and cer

13、ebrovascular risk of celecoxib vs. placebo (Dec. 17, 2004)NIA announced ADAPT trial suspension (Dec. 20, 2004)Information released to public by study group, were based on preliminary findings, not through peer-reviewed journals Sources: Celebrex News Release Dec 17, 2004; NIH News Dec 20, 2004; Wash

14、ingtonpost Feb 1, 2005, written by Woloshin S et al.12SummaryNaproxen is a non-selective COX-1 / COX-2 inhibitorWidely used Established safety profileReference standardUnadjudicated preliminary findings of ADAPT needs to be looked at in context of the wide body of data on naproxen13Martin H. Huber,

15、MDGlobal Head, Drug SafetyHoffmann-La Roche Inc.P-14Safety EvaluationClinical PharmacologyClinical Studies Post-Marketing Safety SurveillancePost-Marketing Clinical StudiesObservational Studies15Pharmacological Difference between Naproxen and COX-2 InhibitorsNaproxen is a non-selective COX-1 /COX-2

16、inhibitorNaproxen is known to inhibit platelet aggregation and thus, is not expected to have an increased risk of myocardial infarction16Clinical Trials and Post-Marketing SurveillanceClinical trials in the prescription and OTC naproxen NDAs did not provide any evidence of an increased risk of myoca

17、rdial infarction or stroke A review of postmarketing surveillance data showed no signal for MI or cerebrovascular accident with exposures to prescription naproxen of more than 110,000,000 patients A review OTC postmarketing surveillance data did not identify a signal for MI or CVA with an estimate o

18、f 550,000,000 courses of therapy17Proportional Reporting Rate (PRR)EventPRRSignificance (P value)Ischemic coronary artery disorders (high-level term)0.160.05MI (preferred terms)0.180.05CNS hemorrhages and cerebrovascular accidents (high level term)0.16 0.05Source: Evans S et al. Pharmacoepidemiology

19、 and Drug Safety 2001; 10: 483-8618Post-Marketing Clinical TrialsVIGORRandomized RA patients 50 yo (or 40 yo and receiving long-term glucocorticoid therapy) into either rofecoxib 50mg qd (N=4,047) or naproxen 500mg bid (N=4,029)Overall rate of cardiovascular events reported in association with napro

20、xen is consistent with that expected in this population MI: Rofecoxib (0.4%) vs. naproxen (0.1%)Ischemic cerebrovascular events: 0.2% in both armsSource: Bombardier C et al. NEJM 2000; 343:1520-819Post-Marketing Clinical TrialsTARGETRandomized OA patients 50 yo into either lumiracoxib 400mg qd (N=9,

21、156), naproxen 500mg bid (N=4,754) or ibuprofen 800mg tid (N=4,415)Naproxen arm showed lower rates for cerebrovascular events and MI:Stroke: Lumiracoxib (0.34%) vs. naproxen (0.25%)Ischemic stroke: Lumiracoxib (0.32%) vs. naproxen (0.23%)Hemorrhagic stroke: 0.02% in both armsAcute MI: Lumiracoxib (0

22、.38%) vs. naproxen (0.23%)Source: Farkouh ME et al. Lancet 2004; 364: 675-8420Post-Marketing Clinical TrialsTARGET (cont.)Rate of MI events was lower for naproxen than ibuprofen, using lumiracoxib as the reference point for both studiesEvent*LumiracoxibIbuprofenCV death0.18%0.23%All MI0.11%0.16%Stro

23、ke0.18%0.20%Source: Farkouh ME et al. Lancet 2004; 364: 675-84* Given in percent of patients with confirmed or probable cardiovascular and cerebrovascular eventsLumiracoxibNaproxen0.23%0.17%0.38%0.21%0.34%0.25%21Additional Post-Marketing Clinical TrialsAlzheimers TrialRandomized mild to moderate AD

24、patients (mean age: 74 yo) into either rofecoxib 25mg qd, naproxen sodium 220mg bid, or placeboSource: Aisen PS et al. JAMA 2003; 289: 2819-26EventsPlacebo(n=111)Naproxen (N=118)Rofecoxib (N=122)Death112MI103Stroke/TIA13322Trials with CelecoxibPooled analysis of 41 celecoxib clinical trials (White e

25、t al)2271 naproxen patients1 non-fatal stroke 1 fatal stroke2 non-fatal MIsNaproxen (relative to celecoxib): 4/393 (1.01 per 100 patient years)Celecoxib (relative to NSAIDs): 56/4,969 (1.13 per 100 patient years)Placebo (relative to celecoxib): 3/200 (1.5 per 100 patient years)There is no evidence o

26、f an increased risk of MI or stroke compared to either celecoxib or placeboSource: White et al. Am J Cardiology 2003; 92: 411-1823Observational StudiesCase control studies and retrospective cohort studies can be performed in a shorter period of timeOpportunity to detect/evaluate relatively infrequen

27、t eventsReflect “real world use of the drug More heterogeneous populationsConcomitant medications, concurrent illnessesValue of observational studies increases when these studies are done in multiple populationsSource: Strom B, Pharmacoepidemiology 2000; Wiley and Sons24Summary of observational studies of naproxen and MISource: Juni et al. Lancet 2004;364:2021-2925Sensitivity Analysis of Observational StudiesMeta-analysis included multiple studies from same databasesPerformed analysis including only one study from